Efficacy of greater occipital nerve block treatment for migraine and potential impact of patient positioning during procedure: Results of randomised controlled trial.

PURPOSE: Assess the efficacy, and potential impact of patient positioning for 10 minutes immediately post-procedure, of greater occipital nerve (GON) block for treatment of migraine. METHODS: Prospective multicentre non-blinded randomised controlled trial, randomisation and treatment of 60 neurology clinic patients with poorly controlled migraine. Outcomes measured with Headache Impact Test-6 (HIT-6), modified MIgraine Disability Assessment Scale (M-MIDAS), and RELIEF scores. RESULTS: Patient positioning did not lead to significant difference in RELIEF score (34% vs 11%, p-value 0.10, Chi-squared test) at day 90. When considered in a multiple regression analysis, the sitting position outperformed supine position significantly (p-value 0.04). However, no significant difference in HIT-6 score between the supine (n = 27) and sitting position groups (n = 33) was detected at baseline (p-value 0.76), day 30 (p-value 0.69) or day 90 (p-value 0.54, Mann-Whitney U-test). The HIT-6 score significantly improved post-GON block, from median 67 (baseline pre-GON) to 59 (day 30) and 62 (day 90) for the supine group and a score of 66, 61-62 for the sitting group (all p-value ≤ 0.001, intra-group comparison using Wilcoxon test); M-MIDAS achieved similar outcomes. Overall, a significant minimal clinically important improvement was obtained with GON block, and the GON injections were deemed very tolerable by patients (median score of 2 on 10 cm pain scale). CONCLUSION: Regardless of patient positioning, GON block is an effective and near-painless procedure for migraine symptom control. Unlike earlier published observational study data, this trial concludes that a sitting patient position immediately post-GON is preferred.

Prevalence and severity of restless leg syndrome in patients with spinal cord injuries.

OBJECTIVE: To determine the prevalence of restless leg syndrome in patients with spinal cord injury using a consensus criterion. METHODS: The cross-sectional study was conducted from November 29, 2018, to February 28, 2021 at the departments of Neurology and Orthopaedic Surgery, King Edward Medical University, Mayo Hospital, Lahore, Pakistan, and comprised patients of either gender aged 18-80 years having spinal cord injuries. All the patients were interviewed using a 10-item questionnaire, and were assessed using the five-point consensus criteria of the International Restless Leg Syndrome Study Group. Data was analysed using SPSS 20. RESULTS: Of the 253 patients, 128(50.6%) were males and 125(49.4%) were females. The overall mean age was 38.6±14.2 years. Restless leg syndrome was present in 116(45.8%) patients, and 64(55.2%) of them were males (p>0.05). The mean duration of the symptoms was 18.9±16.9 months. Causes of spinal cord injury included metastasis 28(11.1%) multiple sclerosis 32(12.6%), neuromyelitis optica spectrum disorders 68(26.9%), tuberculous spondylitis 85(33.6%), trauma 24(9.5%) and viral myelitis 16(6.3%). CONCLUSIONS: Restless leg syndrome was prevalent in less than half the patients having spinal cord injury. It was more prevalent in males compared to females, but the difference was not significant.

Excellent Response to OnabotulinumtoxinA: Different Definitions, Different Predictors.

The identification of patients who can benefit the most from the available preventive treatments is important in chronic migraine. We explored the rate of excellent responders to onabotulinumtoxinA in a multicenter European study and explored the predictors of such response, according to different definitions. A pooled analysis on chronic migraineurs treated with onabotulinumtoxinA and followed-up for, at least, 9 months was performed. Excellent responders were defined either as patients with a ≥75% decrease in monthly headache days (percent-based excellent responders) or as patients with <4 monthly headache days (frequency-based excellent responders). The characteristics of excellent responders at the baseline were compared with the ones of patients with a <30% decrease in monthly headache days. Percent-based excellent responders represented about 10% of the sample, whilst frequency-based excellent responders were about 5% of the sample. Compared with non-responders, percent-based excellent responders had a higher prevalence of medication overuse and a higher excellent response rate even after the 1st and the 2nd injection. Females were less like to be frequency-based excellent responders. Chronic migraine sufferers without medication overuse and of female sex may find fewer benefits with onabotulinumtoxinA. Additionally, the excellent response status is identifiable after the first cycle.

Is There a Gender Difference in the Response to onabotulinumtoxinA in Chronic Migraine? Insights from a Real-Life European Multicenter Study on 2879 Patients.

INTRODUCTION: Migraine is mostly a female disorder because of its lower prevalence in men. Less than 20% of patients included in the available studies on migraine treatments are men; hence, the evidence on migraine treatments might not apply to men. The aims of the present study were to provide reliable information on the effectiveness of onabotulinumtoxinA (BT-A) for chronic migraine in men and to compare clinical benefits between men and women. METHODS: We performed a pooled patient-level gender-specific analysis of real-life data on BT-A for chronic migraine of patients followed-up to 9 months. We reported the 50% responder rates during each BT-A cycle, defined as percentage of reduction in monthly headache days (MHDs) compared to baseline, along with 75% and 30% responder rates. We also reported the mean decrease in MHDs and in days of acute medication use (DAMs) during each BT-A cycle as compared to baseline. We also evaluated the reasons for stopping the treatment within the third cycle. RESULTS: We included an overall cohort of 2879 patients, 522 of whom (18.1%) were men. In men, 50% responder rates were 27.7% during the first BT-A cycle, 29.2% during the second, and 35.6% during the third cycle; in women, the corresponding rates were 26.6%, 33.5%, and 41.0%. In the overall cohort, responder rates did not differ between men and women during the first two cycles; during the third cycle, the distribution was different (P < 0.001) mostly because of higher rates of treatment stopping and non-responders in men. In the propensity score matched cohort, the trend was maintained but lost its statistical significance. Both men and women had a significant decrease in MHDs and in DAMs with BT-A treatment (P < 0.001). There were no gender differences in those changes with the only exception of MHD decrease which, during the third cycle, was lower in men than in women (7.4 vs 8.2 days, P = 0.016 in the overall cohort and 9.1 vs 12.5 days, P = 0.009 in the propensity score matched cohort). At the end of follow-up, 152 men and 485 women stopped BT-A treatment (29.1% vs 20.6%; P < 0.001). The relative proportion of patients stopping treatment because of inadequate response (less than 30% decrease in MHDs from baseline) was higher in men than in women (42.8% vs 39.6%), while the proportion of patients stopping because of adverse events was higher in women than in men (5.6% vs 0%; P = 0.031). CONCLUSIONS: Our pooled analysis suggests that the response to BT-A is significant in both men and women with a small gender difference in favor of women. Men tended to stop the treatment more frequently than women. We emphasize the need for more gender-specific data on migraine treatments from randomized controlled trials and observational studies.

Developments in distinguishing secondary vascular headache from primary headache disorders in clinical practice.

INTRODUCTION: Vascular headaches are secondary headache disorders with potentially devastating consequences if missed. Clinicians often struggle to distinguish these from primary headache disorders whereby there is no underlying structural pathology. Here, the authors describe the advancement in our understanding of vascular headache disorders, their clinical presentation and the developments in neuroimaging that facilitate diagnosis. AREAS COVERED: Here the authors discuss the definition of primary and secondary headache disorders. They review the literature on the presentation, choice of neuroimaging and diagnostic tools that can be used to diagnose specific vascular headaches including Carotid or Vertebral artery dissection, Stroke, Temporal Arteritis, subarachnoid hemorrhage, cerebral venous thrombosis, Reversible Cerebral Vasoconstriction syndrome, Primary angiitis, AV malformation and Genetic vasculopathy. The authors discuss the influence of Covid-19 on the management of patients with headache. EXPERT OPINION: Whilst developments in neuroimaging have been of paramount importance in the diagnosis of vascular headache disorders, there is no substitute for meticulous history taking and examination. Research has aided our understanding of clinical presentation, however further studies are needed as well as increased education of neurologists and acute physicians.

Perception of breast cancer risk factors: Dysregulation of TGF-ß/miRNA axis in Pakistani females.

Breast cancer poses a serious health risk for women throughout the world. Among the Asian population, Pakistani women have the highest risk of developing breast cancer. One out of nine women is diagnosed with breast cancer in Pakistan. The etiology and the risk factor leading to breast cancer are largely unknown. In the current study the risk factors that are most pertinent to the Pakistani population, the etiology, molecular mechanisms of tumor progression, and therapeutic targets of breast cancer are studied. A correlative, cross-sectional, descriptive, and questionnaire-based study was designed to predict the risk factors in breast cancer patients. Invasive Ductal Carcinoma (90%) and grade-II tumor (73.2%) formation are more common in our patient's data set. Clinical parameters such as mean age of 47.5 years (SD ± 11.17), disturbed menstrual cycle (> 2), cousin marriages (repeated), and lactation period (< 0.5 Y) along with stress, dietary and environmental factors have an essential role in the development of breast cancer. In addition to this in silico analysis was performed to screen the miRNA regulating the TGF-beta pathway using TargetScanHuman, and correlation was depicted through Mindjet Manager. The information thus obtained was observed in breast cancer clinical samples both in peripheral blood mononuclear cells, and biopsy through quantitative real-time PCR. There was a significant dysregulation (**P>0.001) of the TGF-ß1 signaling pathway and the miRNAs (miR-29a, miR-140, and miR-148a) in patients' biopsy in grade and stage specifically, correlated with expression in blood samples. miRNAs (miR-29a and miR-140, miR-148a) can be an effective diagnostic and prognostic marker as they regulate SMAD4 and SMAD2 expression respectively in breast cancer blood and biopsy samples. Therefore, proactive therapeutic strategies can be devised considering negatively regulated cascade genes and amalgamated miRNAs to control breast cancer better.

Genome-Wide Association Study Identifies Risk Loci for Cluster Headache.

OBJECTIVE: This study was undertaken to identify susceptibility loci for cluster headache and obtain insights into relevant disease pathways. METHODS: We carried out a genome-wide association study, where 852 UK and 591 Swedish cluster headache cases were compared with 5,614 and 1,134 controls, respectively. Following quality control and imputation, single variant association testing was conducted using a logistic mixed model for each cohort. The 2 cohorts were subsequently combined in a merged analysis. Downstream analyses, such as gene-set enrichment, functional variant annotation, prediction and pathway analyses, were performed. RESULTS: Initial independent analysis identified 2 replicable cluster headache susceptibility loci on chromosome 2. A merged analysis identified an additional locus on chromosome 1 and confirmed a locus significant in the UK analysis on chromosome 6, which overlaps with a previously known migraine locus. The lead single nucleotide polymorphisms were rs113658130 (p = 1.92 × 10-17 , odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.37-1.66) and rs4519530 (p = 6.98 × 10-17 , OR = 1.47, 95% CI = 1.34-1.61) on chromosome 2, rs12121134 on chromosome 1 (p = 1.66 × 10-8 , OR = 1.36, 95% CI = 1.22-1.52), and rs11153082 (p = 1.85 × 10-8 , OR = 1.30, 95% CI = 1.19-1.42) on chromosome 6. Downstream analyses implicated immunological processes in the pathogenesis of cluster headache. INTERPRETATION: We identified and replicated several genome-wide significant associations supporting a genetic predisposition in cluster headache in a genome-wide association study involving 1,443 cases. Replication in larger independent cohorts combined with comprehensive phenotyping, in relation to, for example, treatment response and cluster headache subtypes, could provide unprecedented insights into genotype-phenotype correlations and the pathophysiological pathways underlying cluster headache. ANN NEUROL 2021;90:193-202.

OnabotulinumtoxinA for the prophylactic treatment of headaches in adult patients with chronic migraine: a safety evaluation.

Introduction: Existing oral prophylaxis for chronic migraine (CM) are often ineffective or poorly tolerated. OnabotulinumtoxinA (onabotA) is approved for headache prophylaxis in CM and ameliorates headaches in patients refractory to multiple preventatives.Areas covered: We appraise evidence regarding action mechanisms, pharmacodynamics, and pharmacokinetics of onabotA in CM prophylaxis. We critically evaluate salient clinical and real-world studies demonstrating its efficacy in improving multiple aspects of CM. We discuss onabotA safety, tolerability, and adverse events (AEs) for CM prophylaxis from clinical trials, post-authorization studies and meta-analyses, including novel pregnancy safety data and comparisons with oral prophylactics. We explore areas of future interest, particularly onabotA safety and efficacy in the context of novel antibody-based prophylaxis.Expert opinion: Clinical and real-world evidence demonstrate onabotA safety, tolerability and efficacy for CM prophylaxis. Most AEs are mild/moderate and self-limiting, with few serious AEs and no treatment-related deaths. Common AEs include neck pain, ptosis, muscle weakness, and stiffness. Modifying existing responder-criteria enables more patients to benefit from onabotA. OnabotA shows superior safety and efficacy to oral preventatives, and appears safe in pregnancy. Future pregnancy-risk register will clarify pregnancy and lactation safety further. Future research comparing onabotA safety and efficacy with newly emergent antibody-based prophylaxis is keenly awaited.

Early Management of OnabotulinumtoxinA Treatment in Chronic Migraine: Insights from a Real-Life European Multicenter Study.

INTRODUCTION: OnabotulinumtoxinA (BT-A) quarterly was the first treatment approved specifically for chronic migraine (CM). It is unclear whether three cycles are better than two to assess early BT-A response. METHODS: We performed a retrospective analysis on real-life prospectively collected data in 16 European headache centers. All the centers provided data on patients treated with BT-A for CM over the first three cycles of treatment. For each treatment cycle we defined patients as "good responders" if reporting a ≥ 50% reduction in monthly headache days compared with the three months before starting BT-A, "partial responders" if reporting a 30-49% reduction in monthly headache days, and "non-responders" if reporting a < 30% reduction in monthly headache days or stopping the treatment before the third cycle. RESULTS: We included 2879 patients. Seven hundred and eighty-four (64.6%) of the 1213 patients reporting a good response during the first and/or the second cycle had a good response during the third cycle; 309 (49.3%) of the 627 patients reporting a partial response (but no good response) during the first and/or the second cycle had a good response during the third cycle; only 65 (6.3%) of the 1039 patients who did not respond during both the first two cycles achieved a good response during the third cycle. Multivariate analyses showed that partial or good response during the first or the second cycle were independently associated with good response during the third cycle. CONCLUSIONS: Our data suggest that patients with CM responding to BT-A during the first two cycles will likely benefit from the third cycle of treatment, while the probability that non-responders to the first two cycles start responding during the third cycle is low. These results can help guide the individual decision to stop or continue treatment after the second cycle in patients who have not responded to the first two cycles.

OnabotulinumtoxinA for chronic migraine during pregnancy: a real world experience on 45 patients.

OBJECTIVE: To report the pregnancy outcomes on patients with chronic migraine exposed to onabotulinumtoxinA from Hull Headache Clinic. BACKGROUND: Migraines are common in women of reproductive age and those with chronic migraine have a major impact on their activities of daily living and health-related quality of life. Apart from low dose amitriptyline and beta-blockers all other prophylactic agents have proven teratogenic effects. OnabotulinumtoxinA is approved as preventive treatment for adult patients with chronic migraine, although its impact on pregnancy is unknown. METHODS: We prospectively collected data for efficacy and safety on all patients treated with onabotulinumtoxinA at the Hull Headache Clinic. The toxin is administered as per PREEMPT paradigm. Female patients of reproductive age group receiving onabotulinumtoxinA are given advice on contraception and the unknown impact of the toxin on pregnancy. They are asked to report pregnancy when they are appraised on the risk/benefit of treatment continuation. All patients are consented for access to their medical records and pregnancy outcome and those who wished to continue are asked to sign a disclaimer. Pregnancy outcome data was collected on all patients for the mode of delivery, birth weight and congenital malformation and any other unexpected outcomes. RESULTS: Over 9 years period 45 patients reported pregnancy while receiving onabotulinumtoxinA. All patients had received onabotulinumtoxinA within 3 months prior to the date of conception. 32 patients wished to continue treatment during pregnancy while the remaining 13 stopped treatment. Apart from 1 miscarriage in the treatment group, all patients had full term healthy babies of normal birth weight and no congenital malformations. CONCLUSION: We report our experience of 45 patients exposed to onabotulinumtoxinA during pregnancy. Although the numbers are small, there was no impact of the toxin found on the pregnancy outcomes.

Perceptions, experiences, and understandings of cluster headache among GPs and neurologists: a qualitative study.

BACKGROUND: Cluster headache is a severe primary headache with a similar prevalence to that of multiple sclerosis. Cluster headache is characterised by unilateral trigeminal distribution of pain, ipsilateral cranial autonomic features, and a tendency to circadian and circannual periodicity. AIM: To explore the perceptions, experiences, and understandings of cluster headache among GPs and neurologists. DESIGN AND SETTING: Qualitative interview study in primary care surgeries and neurology departments in the north of England. METHOD: Semi-structured interviews were conducted with GPs and neurologists, recorded, and transcribed. A thematic analysis was applied to the dataset. RESULTS: Sixteen clinicians participated in this study: eight GPs and eight neurologists. Four main themes were identified following thematic analysis: challenges with the cluster headache diagnosis; impact of cluster headache; challenges with treatment; and appropriateness of referrals to secondary care. Clinicians recognised the delays in the diagnosis of cluster headache, misdiagnosis, and mismanagement, and were aware of the potential impact cluster headache can have on patients' mental health and ability to remain in employment. Findings highlighted tensions between primary and secondary care around the cost of medication and the remit of prescribing treatment regimens. Patients' anxiety, their need for reassurance, and their insistence about seeing a specialist are some of the reasons for referrals. CONCLUSION: Clinicians acknowledged delays in diagnosis, misdiagnosis, and mismanagement of cluster headache. The responsibility of prescribing causes ongoing tensions between primary and secondary care. Clear referral and management pathways for primary headaches are required to improve patient outcomes and healthcare costs.

Development and Evaluation of a Screening Tool to Aid the Diagnosis of a Cluster Headache.

Cluster headache (CH), a severe primary headache, is often misdiagnosed and mismanaged. The aim of this study was to develop and evaluate a screening tool to aid the diagnosis of CH. We developed a novel 12-item screening tool. This was comprised of four components: (1) images depicting headache pain; (2) pain descriptors; (3) key questions that could differentiate between CH and migraine; and (4) a visual analogue pain scale. The total possible questionnaire score ranged from 3-32. Patients with CH and migraines (control group) were recruited prospectively from a headache centre in the North of England, UK. Two-hundred and ninety-six patients were included in the study: 81 CH patients, 36 of which suffer with episodic CH and 45 with chronic CH; 215 migraine patients, 92 of which suffer with episodic migraine and 123 with chronic migraine. The mean questionnaire score was higher in CH patients versus migraine patients (28.4 versus 19.5). At a cut-off score of >25 out of 32, the screening tool had a sensitivity of 86.4% and a specificity of 92.0% in differentiating between CH and migraine. The screening tool could be a useful instrument to aid the diagnosis of a CH. The images depicting headache pain do not clearly discriminate between CH and migraine.

Modification of miRNA Expression through plant extracts and compounds against breast cancer: Mechanism and translational significance.

BACKGROUND: Cancer is hyper-proliferative, multi-factorial and multi-step, heterogeneous group of molecular disorders. It is the second most reported disease after heart diseases. Breast carcinoma is the foremost death causing disease in female population worldwide. Cancer can be controlled by regulating the gene expression. Current therapeutic options are associated with severe side effects and are expensive for the people living in under-developed countries. Plant derived substances have potential application against different diseases like cancer, inflammation and viral infections. HYPOTHESIS: The mechanism of action of the medicinal plants is largely unknown. Targeting gene network and miRNA using medicinal plants could help in improving the therapeutic options against cancer. METHODS: The literature from 135 articles was reviewed by using PubMed, google scholar, Science direct to find out the plants and plant-based compounds against breast cancer and also the studies reporting their mechanistic route of action both at coding and noncoding RNA levels. RESULTS: Natural products act as selective inhibitors of the cancerous cells by targeting oncogenes and tumor suppressor genes or altering miRNA expression. Natural compounds like EGCG from tea, Genistein from fava beans, curcumin from turmeric, DIM found in cruciferous, Resveratrol a polyphenol and Quercetin a flavonoid is found in various plants have been studied for their anticancer activity. The EGCG was found to inhibit proliferative activity by modulating miR-16 and miR-21. Similarly, DIM was found to down regulate miR-92a which results to modulate NFkB and stops cancer development. Another plant-based compound Glyceollins found to upregulate miR-181c and miR-181d having role in tumor suppression. It also found to regulate miR-22, 29b and c, miR-30d, 34a and 195. Quercetin having anti-cancer activity induce the apoptosis through regulating miR-16, 26b, 34a, let-7g, 125a and miR-605 and reduce the miRNA expression like miR-146a/b, 503 and 194 which are involved in metastasis. CONCLUSION: Targeting miRNA expression using natural plant extracts can have a reverse effect on cell proliferation; turning on and off tumor-inducing and suppressing genes. It can be efficiently adopted as an adjuvant with the conventional form of therapies to increase their efficacy against cancer progression.

Updated cost-effectiveness analysis of onabotulinumtoxinA for the prevention of headache in adults with chronic migraine who have previously received three or more preventive treatments in the UK.

Aims: OnabotulinumtoxinA is recommended by NICE for the treatment of chronic migraine. This economic evaluation provides updated estimates of the cost-effectiveness of onabotulinumtoxinA for chronic migraine using new utility estimates in an existing model structure.Methods: A previously published model was revised to include EQ-5D utility estimates from a large observational study (REPOSE; n = 633). Efficacy data were taken from the pooled phase III PREEMPT clinical trial program, while resource utilization estimates were obtained from the International Burden of Migraine Study (IBMS). The model estimated costs and quality-adjusted life years (QALYs) gained over 2 years from the UK NHS perspective.Results: OnabotulinumtoxinA treatment resulted in total discounted incremental costs of £1,204 and an incremental discounted QALY gain of 0.07 compared with placebo in patients with chronic migraine who have previously failed three or more preventive treatments, corresponding to an incremental cost-effectiveness ratio (ICER) of £16,306 per QALY gained. Scenario analysis showed that the administration of onabotulinumtoxinA by a specialist nurse rather than a neurology consultant reduced the ICER from £16,306 to £13,832 per QALY gained. Removal of the positive stopping rule recommended in current NICE guidance increased the ICER to £20,768 per QALY for onabotulinumtoxinA vs. placebo. Combining these two scenarios produced an ICER of £17,686 per QALY gained.Conclusion: NICE recommended onabotulinumtoxinA for the prevention of chronic migraine in 2012 amid concerns about the uncertainty of ICER estimates, with a positive stopping rule used to manage some of these uncertainties. Since the publication of the NICE guidance, the REPOSE study provides a more recent source of utility data based on real-world evidence. The results of analyses including these utilities suggest that the application of the positive stopping rule may not be necessary to ensure cost-effectiveness and that this aspect of the current NICE guidance for onabotulinumtoxinA may merit reconsideration.

Images depicting headache pain - a tool to aid the diagnosis of cluster headache: a pilot study.

INTRODUCTION AND OBJECTIVE: The diagnosis of primary headaches is based on the International Classification of Headache Disorders (ICHD-3). Cluster headache (CH), a debilitating primary headache, is often misdiagnosed as migraine. In the absence of biological markers, a new visual screening tool with images depicting pain could aid the correct diagnosis of CH. The objective of the study is to test the tool on healthy participants and participants with CH and migraine. METHODS: In phase 1, 6 images portraying people with pain were tested on 150 healthy participants. The healthy participants were asked to rate the images as mild, moderate, severe or excruciating pain. In phase 2, the images were further tested on 116 participants with headache (16 participants with CH, 100 participants with migraine). The participants were recruited prospectively from a tertiary headache center between February and May 2017. The participants were asked to choose which image best illustrated their headache attacks. RESULTS: Phase 1 results showed that the images represent a range of headache pain severities from mild to excruciating as rated by healthy participants. They rated two images as excruciating, one image as severe, one image as moderate/severe, one image as moderate and one image as mild. Phase 2 results showed that two-thirds of participants with CH (69%) and half of the participants with migraine (52%) chose an image described as excruciating by the healthy participants. CONCLUSION: We developed a screening tool with six drawings depicting headache pain severities from mild to excruciating as rated by the healthy participants. Although the images did not differentiate between CH and migraine, the study indicated the potential of using visual aids to assess headache severity.

Atsttrin reduces lipopolysaccharide-induced neuroinflammation by inhibiting the nuclear factor kappa B signaling pathway.

Progranulin is closely related to neuronal survival in a neuroinflammatory mouse model and attenuates inflammatory reactions. Atsttrin is an engineered protein composed of three progranulin fragments and has been shown to have an effect similar to that of progranulin. Atsttrin has anti-inflammatory actions in multiple arthritis mouse models, and it protects against further arthritis development. However, whether Atsttrin has a role in neuroinflammation remains to be elucidated. In this study, we produced a neuroinflammatory mouse model by intracerebroventricular injection of 1 µL lipopolysaccharide (10 µg/µL). Atsttrin (2.5 mg/kg) was administered via intraperitoneal injection every 3 days over a period of 7 days before intracerebroventricular injection of 1 µL lipopolysaccharide (10 µg/µL). In addition, astrocyte cultures were treated with 0, 100 or 300 ng/mL lipopolysaccharide, with 200 ng/mL Atsttrin simultaneously. Immunohistochemistry, enzyme-linked immunosorbent assay and real-time reverse transcription-polymerase chain reaction were performed to examine the protein and mRNA levels of inflammatory mediators and to assess activation of the nuclear factor kappa B signaling pathway. Progranulin expression in the brain of wild-type mice and in astrocyte cultures was increased after lipopolysaccharide administration. The protein and mRNA expression levels of tumor necrosis factor-α, interleukin-1ß and inducible nitric oxide synthase were increased in the brain of progranulin knockout mice after lipopolysaccharide administration. Atsttrin treatment reduced the lipopolysaccharide-induced increase in the protein and mRNA levels of tumor necrosis factor-α, interleukin-1ß, matrix metalloproteinase-3 and inducible nitric oxide synthase in the brain of progranulin knockout mice. Atsttrin also reduced the expression of cyclooxygenase-2, inducible nitric oxide synthase and matrix metalloproteinase 3 mRNA in lipopolysaccharide-treated astrocytes in vitro, and decreased the concentration of tumor necrosis factor a and interleukin-1ß in the supernatant. Furthermore, Atsttrin significantly reduced the levels of phospho-nuclear factor kappa B inhibitor a in the brain of lipopolysaccharide-treated progranulin knockout mice and astrocytes, and it decreased the expression of nuclear factor kappa B2 in astrocytes. Collectively, our findings show that the anti-neuroinflammatory effect of Atsttrin involves inhibiton of the nuclear factor kappa B signaling pathway, and they suggest that Atsttrin may have clinical potential in neuroinflammatory therapy. The study was approved by the Animal Ethics Committee of Qilu Hospital of Shandong University, China (approval No. KYLL-2015(KS)-088) on February 10, 2015.

An open-label prospective study of the real-life use of onabotulinumtoxinA for the treatment of chronic migraine: the REPOSE study.

BACKGROUND: The PREEMPT Studies established onabotulinumtoxinA as preventive treatment for adults with chronic migraine (CM). The purpose of the REal-life use of botulinum toxin for the symptomatic treatment of adults with chronic migraine, measuring healthcare resource utilisation, and Patient-reported OutcomeS observed in practice (REPOSE) Study was to observe real-life, long-term (24-month) use of onabotulinumtoxinA in adults with CM and report on the utilisation, effectiveness, safety, and tolerability. METHODS: The REPOSE Study was a European, open-label, multicentre, prospective, noninterventional study. Patients received onabotulinumtoxinA approximately every 12 weeks according to their physician's usual practice, guided by the summary of product characteristics (SPC). Patients were observed for 24 months after initiating onabotulinumtoxinA treatment. Outcome measures were collected at baseline and all administration visits and included onabotulinumtoxinA injection practices, headache-day frequency, Migraine-Specific Quality-of-Life Questionnaire (MSQ), EuroQol 5-Dimension Questionnaire (EQ-5D), and adverse drug reactions (ADRs) to evaluate safety/tolerability. RESULTS: Of 641 patients enrolled, 633 received ≥1 dose of onabotulinumtoxinA for a total of 3499 treatment sessions. At baseline, mean (SD) age was 45.4 (11.7) years; patients were predominantly women (85.3%). Injection practices closely followed the SPC in mean dosage (155.1 U) and injection sites per session (31.4), with the exception of a prolongation of the recommended 12-week dosing interval, with 79.1% of patients receiving ≥1 treatment session that was > 13 weeks after the previous treatment session. Headache-day frequency was reduced from a baseline mean (SD) of 20.6 (5.4) to 7.4 (6.6) days at administration visit 8 (P < 0.001). Each MSQ domain (restrictive, preventive, and emotional) was significantly reduced from baseline through each administration visit (P < 0.001). The median EQ-5D total and health state scores were significantly improved from baseline through each administration visit (P < 0.001). Overall, 18.3% of patients reported an ADR; most were mild to moderate intensity, with only 1.3% of patients reporting a serious ADR. Eyelid ptosis (5.4%), neck pain (2.8%), and musculoskeletal stiffness (2.7%) were the most frequently reported. CONCLUSIONS: Long-term, real-world preventive treatment of CM with onabotulinumtoxinA showed effectiveness with a sustained reduction in headache-day frequency and significant improvement in quality-of-life measures. ADRs were mild to moderate, with no new safety concerns identified. TRIAL REGISTRATION: Trial registration number: NCT01686581. Name of registry: ClinicalTrials.gov. URL of registry: https://clinicaltrials.gov/ct2/show/NCT01686581 . Date of retrospective registration: September 18, 2012. Date of enrolment of first patient: July 23, 2012.

Characteristics and advantages of adeno-associated virus vector-mediated gene therapy for neurodegenerative diseases.

Common neurodegenerative diseases of the central nervous system are characterized by progressive damage to the function of neurons, even leading to the permanent loss of function. Gene therapy via gene replacement or gene correction provides the potential for transformative therapies to delay or possibly stop further progression of the neurodegenerative disease in affected patients. Adeno-associated virus has been the vector of choice in recent clinical trials of therapies for neurodegenerative diseases due to its safety and efficiency in mediating gene transfer to the central nervous system. This review aims to discuss and summarize the progress and clinical applications of adeno-associated virus in neurodegenerative disease in central nervous system. Results from some clinical trials and successful cases of central neurodegenerative diseases deserve further study and exploration.

Update on the pathophysiology of cluster headache: imaging and neuropeptide studies.

OBJECTIVE: Cluster headache (CH) is the most severe primary headache condition. Its pathophysiology is multifaceted and incompletely understood. This review brings together the latest neuroimaging and neuropeptide evidence on the pathophysiology of CH. METHODS: A review of the literature was conducted by searching PubMed and Web of Science. The search was conducted using the following keywords: imaging studies, voxel-based morphometry, diffusion-tensor imaging, diffusion magnetic resonance imaging, tractography, connectivity, cerebral networks, neuromodulation, central modulation, deep brain stimulation, orexin-A, orexin-B, tract-based spatial statistics, single-photon emission computer tomography studies, positron-emission tomography, functional magnetic resonance imaging, magnetic resonance spectroscopy, trigeminovascular system, neuropeptides, calcitonin gene-related peptide, neurokinin A, substance P, nitric oxide synthase, pituitary adenylate cyclase-activating peptide, vasoactive intestinal peptide, neuropeptide Y, acetylcholine, noradrenaline, and ATP. "Cluster headache" was combined with each keyword for more relevant results. All irrelevant and duplicated records were excluded. Search dates were from October 1976 to May 2018. RESULTS: Neuroimaging studies support the role of the hypothalamus in CH, as well as other brain areas involved in the pain matrix. Activation of the trigeminovascular system and the release of neuropeptides play an important role in CH pathophysiology. Among neuropeptides, calcitonin gene-related peptide, vasoactive intestinal peptide, and pituitary adenylate cyclase-activating peptide have been reported to be reliable biomarkers for CH attacks, though not specific for CH. Several other neuropeptides are involved in trigeminovascular activation, but the current evidence does not qualify them as reliable biomarkers in CH. CONCLUSION: CH has a complex pathophysiology and the pain mechanism is not completely understood. Recent neuroimaging studies have provided insight into the functional and structural network bases of CH pathophysiology. Although there has been important progress in neuropeptide studies, a specific biomarker for CH is yet to be found.